The present invention relates to a novel method for preparing 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid, also known as Rebamipide represented by the formula I and useful for treatment of peptic ulcer from alkyl 2-(4-chlorobenzoylamino)-2-alkoxycarbonyl-3-[2(1H)-quinolinon-4-yl]propionate represented by the formula II in the presence of a base solution for hydrolysis and decarboxylation to remove a carboxyl group: 
where R1 and R2 are lower alkyl or aryl.
In general, the conventional method for preparing the compound of the formula I involves the reaction of 4-bromomethylcarbostyril represented by the formula VII with diethyl acetamidomalonate represented by the formula. VIII in the presence of sodium ethylate as a base to prepare ethyl 2-acetamido-2-carboethoxy-3-[2(1H)-quinolinon-4-yl]propionate represented by the formula IX, the hydrolysis of the ethyl 2-acetamido-2-carboethoxy-3-[2(1H)-quinolinon-4-yl]propionate in 20% hydrochloric acid to prepare 2-amino-3-[2(1H)-quinolinon-4-yl]propionic acid hydrochloride represented by the formula X, and the condensation reaction of 2-amino-3-[2(1H)-quinolinon-4-yl]propionic acid hydrochloride with 4-chlorobenzoylchloride represented by the formula XI in the presence of potassium carbonate as a base to prepare 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid, also known as Rebamipide represented by the formula I. This preparation process can be expressed by the scheme 1: 
The conventional preparation method is disadvantageous in the two following aspects. First, the hydrolysis of the compound of the formula IX to prepare the compound of the formula X involves more than 9 hours of reflux stirring using a halogenated hydracid such as 20% hydrochloric acid or hydrobromic acid. The use of such a dangerous strong acid as hydrochloric acid or hydrobromic acid causes a problem in regard to work stability and the flux stirring at a high temperature for a long time consumes much energy. So the preparation process is uneconomical and not friendly to the environment.
Second, the compound of the formula X prepared by the hydrolysis of the compound of the formula IX is no more than an intermediate and has to be reacted with the compound of the formula XI for condensation reaction in order to yield the title compound of the formula I. This makes the process long and thus reduces the yield.
In an attempt to solve the problems with the prior art, the inventors of the present invention have explored a novel preparation method that provides a high yield with a more economical, safer and simpler process.
Accordingly, it is an object of the present invention to provide a novel method for preparing 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid, so-called Rebamipide that is a material for treatment of peptic ulcer.
In an aspect of the present invention, there is provided a method for providing, with a high yield, 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid, also known as Rebamipide represented by the formula I and useful for treatment of peptic ulcer: 
More specifically, as shown in the following scheme 2, the present invention is to provide a method for preparing Rebamipide of the formula I with high yield (92%) and purity that includes subjecting the compound of the formula II to both hydrolysis and decarboxylation in the presence of a base at a temperature of xe2x88x9210 to 80xc2x0 C., preferably 50 to 60xc2x0 C. in an alcoholic solvent or a mixed solvent of at least one alcohol and water for 2 hours: 
where R1 and R2 are lower alkyl or aryl.
In the preparation method of the present invention, the base solution used for the hydrolysis of the compound of the formula II may include, if not specifically limited to, sodium hydroxide or potassium hydroxide solution. The compound of the formula II is reacted in a mild condition, for example, at a preferable temperature of about 50 to 60xc2x0 C. for about 2 hours for selective hydrolysis of the ester group and decarboxylation to yield the title compound of the formula I.
As an intermediate in the present invention, the compound of the formula II is prepared simply by reacting the compound of the formula IV with 4-halomethylquinolinon of the formula III in the presence of sodium ethylate with reflux stirring for 2 hours for condensation reaction, which process can be expressed by: 
where R1 and R2 are as defined above; and X is halide.
Preferably, the compound of the formula II prepared by the scheme 3 is not isolated or purified but the reactant solution is subjected to thin layer chromatography to check the termination of the reaction, immediately after which the compound of the formula I is yielded according to the scheme 2. The overall preparation process can be expressed by: 
where R1, R2 and X are as defined above.
The method for preparing Rebamipide of the formula I without a step of isolating and purifying the compound of the formula II can be summarized as follows. First, the compound of the formula II is prepared by reacting the compound of the formula IV with the compound of the formula III in the presence of sodium ethylate at the room temperature with stirring for 16 hours for condensation reaction. Without isolation or purification of the compound of the formula II, the reactant solution containing the compound of the formula II is subjected to both hydrolysis and decarboxylation in the presence of a base at a temperature of xe2x88x9210 to 80xc2x0 C., preferably 50 to 60xc2x0 C. in an alcoholic solvent or a mixed solvent of at least one alcohol and water for about 2 hours to produce Rebamipide of the formula I with high yield and purity.
In the case of preparing Rebamipide of the formula I without isolation or purification of the compound of the formula II according to the present invention, the compound of the formula II is subjected to a reaction in a mild condition at the room temperature instead of reflux stirring in the synthesis process, thereby increasing the yield, and the step of isolation or purification is eliminated to reduce the complexity of the process.
On the other hand, the compound of the formula IV is simply prepared from the compound of the formula V and the compound of the formula VI, normally 4-chlorobenzoylchloride according to the following scheme 5: 
where R1 and R2 are as defined above; and Xxe2x80x2 is halogen or hydroxy.
The preparation method of the present invention includes no more than one or two reaction steps to prepare the title compound of the formula I from the compound of the formula III without the complicated reaction step of the prior art that requires strict conditions, thereby reducing the number of reaction steps for the preparation process, and needs a mild condition (for example, low reaction temperature) without using such a strong acid as hydrochloric acid or hydrobromic acid. So the present invention provides an environment-friendly and economical method for preparing Rebamipide of the formula I with a high yield (about 92%).
If necessary, the title compound of the formula I in the present invention is convertible to its physiologically or pharmaceutically acceptable hydrate and/or acid addition salt.
Hereinafter, the present invention will be described in detail by way of the following examples, which are not intended to limit the scope of the present invention.